Helen R. Winter

Pharmacokinetic profiles of extended release quetiapine fumarate compared with quetiapine immediate release

This 10-day, single-center, open-label, randomized, crossover study compared pharmacokinetic profiles and tolerability of extended release quetiapine fumarate (quetiapine XR) with quetiapine immediate release (quetiapine IR) in patients with schizophrenia, schizoaffective disorder or bipolar disorder. After a 2-day lead-in period during which patients received quetiapine XR 300 mg once daily, patients were randomized to quetiapine IR 150 mg twice daily followed by quetiapine XR 300 mg once daily, or quetiapine XR 300 mg once daily followed by quetiapine IR 150 mg twice daily. Pharmacokinetic parameters were evaluated at the end of each 4-day treatment period at steady state. Vital signs, laboratory values, and adverse events (AEs) were recorded throughout the study. The least squares means (90% confidence interval) of the ratio of the area under the plasma concentration-time curve over a 24 h dosing interval (AUC ([0-24 h])) for quetiapine XR/IR was 1.04 (0.92-1.19) and within the pre-defined range set for equivalence (0.80-1.25). Maximum plasma concentration at steady state (C(max)) was approximately 13% lower for quetiapine XR than for quetiapine IR (495.3 versus 568.1 ng/mL), time to reach C(max) (t(max)) was 5 h versus 2 h and mean concentration at the end of 24 h dosing interval (C(min)) was 95.3 versus 96.5 ng/mL, respectively. No patients withdrew from the study owing to AEs and there were no serious AEs or deaths related to study medication. No unexpected AEs, changes in vital signs or laboratory values were observed. These findings suggest that modifying the formulation does not change the overall absorption or elimination of quetiapine, and support emerging clinical evidence for the use of quetiapine XR as a once daily treatment in patients initiating therapy or those established on quetiapine IR.

Steady-State Pharmacokinetic, Safety, and Tolerability Profiles of Quetiapine, Norquetiapine, and Other Quetiapine Metabolites in Pediatric and Adult Patients with Psychotic Disorders

OBJECTIVE The aim of this study was to investigate the steady-state pharmacokinetic, safety, and tolerability profiles of immediate-release quetiapine administered by similar dose-escalation regimens in pediatric and adult populations with psychotic or mood disorders. METHODS Pediatric patients aged 10-17 years were titrated to a quetiapine dose of 200 mg twice daily (b.i.d. on days 5-7, 400 mg b.i.d. on days 11-12, with a final 400-mg dose on day 13. In a separate trial, adult patients aged 18-45 years were titrated to a quetiapine dose of 200 mg b.i.d. on days 4-6, 400 mg b.i.d. on days 10-11, with a final 400-mg dose on day 12. Concentrations of quetiapine and three metabolites (quetiapine sulfoxide, 7-hydroxy quetiapine, and norquetiapine) were quantified in plasma and urine. Adverse events, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory tests were evaluated throughout the studies. RESULTS In both pediatric and adult populations, plasma concentrations of quetiapine and norquetiapine increased proportionately as the dose was escalated from 200 mg b.i.d. to 400 mg b.i.d. There were no age-related differences in the dose-normalized quetiapine plasma concentration-time curve (AUC(SS)) and maximum plasma concentration (C(SS,max)). Quetiapine was rapidly absorbed after 200-mg and 400-mg doses in pediatric patients [median t(max) (time to maximum plasma concentration) 1.5 hours, both doses] and adult patients (median t(max) 1.0 hour and 1.2 hours, respectively). The mean quetiapine t(1/2) (terminal elimination half-life) was approximately 6 hours for pediatric and 5 hours for adult patients. Norquetiapine displayed a similar median t(max) and a longer t(1/2) compared with quetiapine. Quetiapine was well tolerated, with no serious adverse events and no unexpected events reported. CONCLUSION Pediatric and adult populations demonstrated similar pharmacokinetic, safety, and tolerability profiles for quetiapine administered by dose escalation. The predictability in quetiapine concentration profiles for children aged 10 years to adults suggests that no dosage adjustment may be required when treating patients of these ages.

The effect of clarithromycin, fluconazole, and rifabutin on dapsone hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283)

Sulfamethoxazole hydroxylamine formation, in combination with long‐term oxidative stress, is thought to be the cause of high rates of adverse drug reactions to sulfamethoxazole in human immunodeficiency virus (HIV)–infected subjects. Therefore the goal of this study was to determine the effect of fluconazole, clarithromycin, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with HIV‐1 infection.

Population pharmacokinetic model of omeprazole following single oral doses in pediatric subjects

To examine the effect of developmental changes on omeprazole (OME) pharmacokinetics (PK) in pediatric subjects.